The long range objective of this project is to develop better pharmacological strategies for treatment of neuropathic pain. Our specific goal here is to study the efficacy of opioid therapy for treatment of neuropathic pain. Because tricyclic antidepressant therapy (e.g. amitriptyline) is often considered the drug of choice for treatment of neuropathic pain, we wish to compare opioid therapy with tricyclic therapy. We have elected to focus in this study on post-herpetic neuralgia (PHN). We do this because PHN is common, PHN provides a homogeneous disease population, PHN has been studied in other clinical research trials, and present therapies are inadequate. Although tricyclic antidepressants have been used for the treatment of PHN, their effects on affective and cognitive functions have not been systematically assessed. In our preliminary studies open-label trials with opiates for treatment of PHN have yielded favorable outcomes. We propose to compare placebo, amitriptyline, and a long-acting preparation of morphine with regard to pain relief, and effects on affective and cognitive function. Effects of treatment, including complications, will be correlated with measures of lifetime and current psychiatric co-morbidity, particularly depression. Patients (N=120) with persistent pain for 3 months or longer will be enrolled in this randomized, blinded, placebo-controlled, cross- over study. After completing a drug-free baseline period, each patient will undergo 3 four-week treatment periods consisting of a placebo, amitriptyline, and morphine. Patients will be randomly assigned to one of the 6 possible orders in which the three treatments can be given. The treatment periods will be preceded by a drug wash-out period and a period for titration to maximal effect. The outcome measures will assess pain intensity, pain relief, psychophysical measures of hyperalgesia, cognition, mood and interference/impairment of function. Psychiatric screening will occur throughout the study, using structured diagnostic instruments. These measurements will be made before the first drug period, and during each of the three treatment periods. This study will contribute to our understanding of tricyclic and opioid therapy for treatment of neuropathic pain. Moreover, this study will help advance the field of clinical trials research as it applies to the study of pain. Lessons derived from this study will lead to further comparative studies of drugs that will impart patient care and cast light on the pathophysiological basis of neuropathic pain states.